492
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`Journal of the Royal Society of Medicine Volume 77 June 1984
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`Quality of life after cytotoxic chemotherapy:
`discussion paper'
`
`T J Priestman MD FRCR
`Consultant in Radiotherapy and Oncology
`Queen Elizabeth and Dudley Road Hospitals, Birmingham
`
`Introduction
`Cytotoxic chemotherapy is the art of differential poisoning, the aim being to destroy the
`tumour before the drugs kill the patient. Unfortunately, it is still distressingly easy to get the
`balance wrong. Although some 40 different cytotoxic drugs are currently commercially
`available in the UK, all suffer from the same fundamental defect: an inability to distinguish
`between normal and malignant cells. Thus all dividing cells within the body are at risk and
`some degree of toxicity is inevitable. Almost all these drugs will cause some degree of bone
`marrow suppression and give rise to subjective symptoms of anorexia, nausea and vomiting.
`In addition, individual agents have specific toxicities which may well cause the patient
`distress, for example, alopecia (with doxorubicin, cyclophosphamide and others), and
`painful peripheral neuropathy (with the vinca alkaloids and cis-platinum).
`Despite these disadvantages, there have been some notable successes following the use of
`cytotoxic drugs in malignant disease. Over the last twenty years, survival in acute lymphatic
`leukaemia in children has risen from virtually zero to well over 50% (Mauer & Simone 1976)
`and in the later stages of Hodgkin's disease, which was also previously incurable, ten-year
`survival figures are of the order of 75% (DeVita 1981). These cancers, however, account for
`less than 5% of all malignant disease and the great majority of our patients suffer from
`carcinomas and sarcomas, the solid tumours. In these conditions, once patients have
`developed local recurrence or metastatic disease after initial radiotherapy or surgery, only
`about 1% may be cured by intensive cytotoxic therapy (testicular teratomas being the major
`example). In patients with carcinoma of the ovary, carcinoma of the breast and small-cell
`cancer of the lung, survival times can be increased, but cure is virtually unknown. For a
`number of other carcinomas, including those of the gastrointestinal tract and head and neck,
`there is a relatively small (20 to 30%) chance of transient tumour shrinkage with drug
`treatment, but no evidence of improved survival. For most remaining cancers, including
`carcinomas of the bladder, uterus and kidney, cytotoxic drugs have virtually nothing to
`offer. Overall it has been estimated that, taking all advanced or inoperable cancers, only
`some 4% are potentially curable by cytotoxic drugs and less than 20% may expect
`prolongation of survival as a result of these agents (DeVita 1982)
`Given the severe toxicities of many of the agents used, it is, therefore, important to assess
`the relative risks and benefits before embarking on treatment, particularly for those patients
`in whom cure or improved survival is unlikely. In order to do this as accurately as possible,
`some form of measurement of subjective parameters is necessary, as well as objective
`measurement of tumour shrinkage. This was recognized as long ago as 1948 when
`Karnofsky developed his ten-point rating scale (Karnofsky & Burchenal 1948) (Table 1).
`This has been criticized on the one hand for being too superficial in that it assesses only
`physical aspects of the patient's condition and is assessed by an observer (usually the
`physician) rather than the patient himself. On the other hand, the scale has been criticized as
`too complex and attempts have been made to simplify the number of categories from ten to
`five or four. By the mid 1970s, however, when the limitations of cytotoxic therapy,
`particularly in the solid tumours, were becoming recognized, the need for a more sensitive
`'Paper read to Section of Comparative Medicine, 30 November 1983. Accepted 2 March 1984
`
`0 141-0768/84/060492-04/$O 1.00/0
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`.1984 The Royal Society of Medicine
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`Journal of the Royal Society of Medicine Volume 77 June 1984
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`493
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`Table 1. The Karnofsky scale (Karnofsky & Burchenal 1948)
`
`Normal
`Minor signs or symptoms
`Normal activity with effort
`Unable to continue normal activity but cares for self
`Requires occasional assistance with personal needs
`Disabled
`Requires considerable assistance and medical care
`Severely disabled and in hospital
`Very sick: active support treatment necessary
`Moribund
`
`10
`9
`8
`7
`6
`5
`4
`3
`2
`1
`
`measure of subjective toxicity was apparent and since that time a number of systems have
`been devised and tested. What follows is a personal account of experience with two such
`methods.
`
`LASA
`Linear analogue self-assessment (LASA) is a standard form of psychological testing. The
`technique is as follows: in order to answer a given question, for example 'How tired do you
`feel today?', a 10 cm line is drawn and the ends of the line labelled with the extremes of the
`parameter being measured, thus 'Not at all' and 'Very tired indeed'. The patient is then
`asked to mark on the line where they fall between those two extremes. The distance along
`the line from one end to the patient's mark can then be measured and a score out of ten
`obtained. In 1975, in collaboration with Professor Baum, a twenty-five point linear
`analogue questionnaire was devised. This included ten aspects related to symptoms of
`disease and side effects of treatment (e.g. pain, nausea), five relating to psychological
`problems (e.g. anxiety, depression), five relating to physical aspects and five covering
`personal relationships. After an initial pilot study to test the reliability of the technique
`(Priestman & Baum 1976), the questionnaire was used to measure subjective effects of
`treatment in a prospectively randomized study comparing endocrine and cytotoxic therapy
`in women with advanced breast cancer.
`The objective results of treatment have been reported previously (Priestman et al. 1978) as
`have the details of subjective evaluation (Baum et al. 1980). In summary, the patients
`receiving cytotoxic therapy experienced a far greater incidence of treatment-related side
`effects than those on hormonal treatment, but overall scored significantly better for general
`well-being. It was felt that this apparent paradox was explained by the difference in objective
`response between the two groups: 49% compared to 21% (P< 0.02), and that the toxicity of
`treatment experienced by the cytotoxic-treated patients was more than offset by the
`symptomatic relief they experienced as a result of objective tumour shrinkage. This view was
`reinforced by an analysis of the cytotoxic-treated patients, comparing responders with
`non-responders, where it was clear that if response was not apparent within 6-8 weeks of
`commencing therapy then side effects rapidly became intolerable. We concluded, therefore,
`that provided objective tumour regression was seen, even quite severe side effects such as
`persistent nausea and vomiting and alopecia were well-tolerated, but that if no response was
`apparent treatment toxicity soon became unbearable.
`This observation has considerable relevance to patients undergoing adjuvant cytotoxic
`therapy. In this situation all clinical disease has been removed by primary surgery or
`irradiation and treatment is given because of the possible presence of micrometastases which
`might be destroyed by drug therapy. The patient has no definite measure of the success of
`treatment and, therefore, side effects are likely to become a major preoccupation. Two
`studies which have set out to measure the subjective impact of adjuvant chemotherapy
`would seem to confirm this view. Palmer and his colleagues (1980) at the Royal Marsden
`Hospital used a detailed questionnaire to assess subjective toxicity and found that 79% of
`patients receiving combination cytotoxic therapy found treatment interfered with their
`
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`494
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`Journal of the Royal Society of Medicine Volume 77 June 1984
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`lifestyle and of these 29% found treatment unbearable. In Manchester, Maguire et al. (1980)
`used present-state interviews to assess psychiatric morbidity and found an overall incidence
`of 81% for problems such as anxiety, depression and sexual problems in women receiving
`chemotherapy compared to 50% in those who underwent mastectomy alone.
`
`EORTC questionnaire
`In 1979 the European Organization for Research and Treatment of Cancer (EORTC)
`formed a Study Group to look at the evaluation of quality of life in cancer patients.
`Following initial discussions within the Group, Dutch psychologists, led by Dr Fritz van
`Dam at the Antoni von Leuvenhoekhuis, prepared a preliminary questionnaire for
`evaluation in clinical trials. This comprised some thirty-five questions: twelve related purely
`to physical performance and were simply answered yes or no; ten related to mood but were
`phrased positively (e.g. 'Yesterday I had the feeling things were going my way') and the
`patient had to answer from one of seven options ranging from 'Very much so' to 'Not at all';
`eleven questions again related to mood but were negatively phrased (e.g. 'Yesterday I felt
`depressed') and the patient chose from six options; finally there were two global questions
`relating to overall well-being with six and seven options for reply respectively.
`We have recently used this questionnaire as part of an evaluation of high-dose
`medroxyprogesterone acetate (MPA) therapy in women with advanced breast cancer
`(Johnson et al. 1983). One reason for being particularly anxious to monitor subjective
`rcsponse in this series was that previous reports had suggested that the increase in appetite,
`pain relief and improved performance status, resulting in an improved quality of life, were
`sometimes seen in the absence of objective tumour shrinkage.
`Scores for subjective assessment were available for 5 patients who had an objective
`response and 12 with progressive disease. The final method of analysis for the subjective
`assessment questionnaires has yet to to be determined, but in our series sequential total
`scores for each patient were compared with the baseline, pre-treatment score, in order to
`ascertain whether, during MPA therapy, individual scores rose (indicating improved well-
`being) or fell (indicating a deterioration in quality of life). The mean change in scores with
`time for responders and treatment failures is shown in Figure 1. Overall the responders'
`scores rose above pre-treatment levels whilst on MPA, whilst those for non-responders fell.
`A repeated measures analysis of variance for the 5 responders and 10 non-responders who
`had completed data over the first eight weeks of treatment showed that the mean difference
`in score between the two groups was statistically significant (P = 0.04). There was a
`tendency for the scores to decline with time in both groups and an overall negative linear
`relationship between score and time was just significant in the responders (P <0.05) but not
`in the non-responders (0.10<P>0.05). However, the heterogeneity of regression was also
`highly significant in both groups (P<0.01, P<0.001). There were marked fluctuations in
`scores for individuals, and Figure 2 charts an example of this. Here the patient's score
`reflected the progress not of her own disease, which steadily improved to complete
`remission, but the fluctuations of her husband's terminal illness.
`Work has continued to define the optimum method for analysis of the subjective data, but
`these results suggest that the EORTC method may be an accurate measure of day-to-day
`quality of life in the individual, but that this does not necessarily correlate with the effects of
`treatment. Certainly there was no evidence from our survey to support the view that MPA
`has a euphoriant effect in those who fail to achieve an objective remission. Equally, however,
`there was no evidence that high MPA levels decreased the quality of life.
`
`Conclusions
`The two methods described, and in particular the linear analogue technique, give us accurate
`and sensitive tools for measuring subjective toxicity. They also provide a basis for relating
`this toxicity to the more global concept of quality of life, though it must be conceded that
`this is an area where further refinement is needed.
`
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`Journal of the Royal Society of Medicine Volume 77 June 1984
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`495
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`20-
`
`01 -lI
`
`RESPONDERS
`
`LU50-
`
`'15
`
`X
`
`-20.
`0
`
`2
`
`4
`
`6
`
`.
`8
`
`10
`
`12
`
`14
`
`PROGRESSION
`(In-l12\
`18
`
`S
`16
`
`i
`
`2
`
`o
`
`TIME
`IN
`WEEKS
`Figure 1. Change in subjective scores during high-dose MPA
`therapy for responders and patients with progressive disease
`
`0
`
`4
`
`8
`
`12
`
`16
`
`al
`
`TIME
`IN WEEKS -
`Figure 2. Changes in subjective score
`during high-dose MPA therapy for
`Mrs MB
`
`I do feel, however, that we have now reached a stage where these systems should be
`incorporated in all new cytotoxic drug evaluations and comparative trials of different agents
`in order to document accurately the subjective impact of therapy, and thus define more
`critically the real place for cancer chemotherapy which at present is almost certainly used
`far too often in completely inappropriate situations where the only results are enormous
`expense to the Health Service and extreme distress to the patient.
`
`References
`Baum M, Priestman T, West R R & Jones E M (1980) European Journal of Cancer, Suppl 1; pp 223-226
`DeVita V T (1981) Cancer 47, 1-13
`DeVita V T (1982) In: Principles and Practice of Oncology. Ed. V T DeVita et al. Lippincott, Philadelphia; pp
`132-135
`Johnson J R, Fotherby K, Priestman S & Priestman T J (1983) Clinical Oncology 9, 180
`Karnofsky D A & Burchenal J H (1948) In: Evaluation of Chemotherapeutic Agents. Ed. C M MacLeod. Columbia
`University Press, New York; p 191
`Maguire G P, Tait A, Brooke M et al. (1980) British Medical Journal 281, 1179-1180
`Mauer A M & Simone J V (1976) Cancer Treatment Reviews 3, 17-41
`Palmer B V, Walsh G A, McKinna J A & Greening W P (1980) British Medical Journal 281, 1594-1597
`Priestman T & Baum M (1976) Lancet i, 899-901
`Priestman T, Baum M, Jones V & Forbes J (1978) British Medical Journal ii, 1673-1674
`
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